Withdrawal of Tiratricol Treatment in Males with Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency): a Double-blind, Randomized, Placebo-controlled Study

This is a double-blind, randomized phase 3 multicenter placebo-controlled study in at least 16 evaluable male participants diagnosed with MCT8 deficiency. Male participants, from 4 years of age (at randomization) and having demonstrated stable maintenance treatment with tiratricol, will be randomized to receive placebo or tiratricol for 30 days or until reaching rescue criterion (serum total triiodothyronine [T3] > upper limit of normal [ULN] of the participant's normal range, for a sample collected during the 30-day Randomized Treatment Period). The research hypothesis to be tested is that, for participants in the placebo group, removal of tiratricol will lead to an increase of serum total T3 concentration, measured by liquid chromatography with tandem mass spectrometry (LC/MS/MS), above the ULN and requirement of rescue treatment with tiratricol, compared to those who continue to receive tiratricol.

开始日期2023-07-21

申办/合作机构

Rare Thyroid Therapeutics International AB

[+2]

CTIS2024-516124-34-00 / Recruiting

Withdrawal of Tiratricol Treatment in Males with Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency): A Doubleblind, Randomized, Placebocontrolled Study (MCT8-2021-3 (ReTRIACt)) - MCT8-2021-3

开始日期2023-07-21

申办/合作机构

Rare Thyroid Therapeutics International AB

ISRCTN98332431 / Completed临床1期

Bioequivalence of two tiratricol tablets and relative bioavailability of tiratricol in the fasted and fed state in healthy male subjects combined with an assessment of dose-proportionality: a randomised, five-period crossover study

开始日期2023-07-06

申办/合作机构

Rare Thyroid Therapeutics International AB

100 项与替拉曲可相关的临床结果

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100 项与替拉曲可相关的转化医学

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100 项与替拉曲可相关的专利（医药）

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项与替拉曲可相关的文献（医药）

2024-10-01·World Journal of Microbiology and Biotechnology

Metabolomic analysis in Amycolatopsis keratiniphila disrupted the competing ECO0501 pathway for enhancing the accumulation of vancomycin.

Article

作者: Chen, Shuo ; Chen, Daijie ; Qian, Xiuping ; Hu, Mengyi ; Rao, Min ; Ge, Mei ; Jin, Wenxiang ; Mao, Wenwei

Vancomycin is a clinically important glycopeptide antibiotic against Gram-positive pathogenic bacteria, especially methicillin-resistant Staphylococcus aureus. In the mutant strain of Amycolatopsis keratiniphila HCCB10007 Δeco-cds4-27, the production of ECO-0501 was disrupted, but enhanced vancomycin yield by 55% was observed compared with the original strain of A. keratiniphila HCCB10007. To gain insights into the mechanism of the enhanced production of vancomycin in the mutant strain, comparative metabolomics analyses were performed between the mutant strain and the original strain, A. keratiniphila HCCB10007 via GC-TOF-MS and UPLC-HRMS. The results of PCA and OPLS-DA revealed a significant distinction of the intracellular metabolites between the two strains during the fermentation process. 64 intracellular metabolites, which involved in amino acids, fatty acids and central carbon metabolism, were identified as differential metabolites. The high-yield mutant strain maintained high levels of glucose-1-phosphate and glucose-6-phosphate and they declined with the increases of vancomycin production. Particularly, a strong association of fatty acids accumulation as well as 3,5-dihydroxyphenylacetic acid and non-proteinogenic amino acid 3,5-dihydroxyphenylglycine (Dpg) with enhancement of vancomycin production was observed in the high-yield mutant strain, indicating that the consumption of fatty acid pools might be beneficial for giving rise to 3,5-dihydroxyphenylacetic acid and Dpg which further lead to improve vancomycin production. In addition, the lower levels of glyoxylic acid and lactic acid and the higher levels of sulfur amino acids might be beneficial for improving vancomycin production. These findings proposed more advanced elucidation of metabolomic characteristics in the high-yield strain for vancomycin production and could provide potential strategies to enhance the vancomycin production.

2024-09-16·The Journal of Clinical Endocrinology & Metabolism

Glycerol Phenylbutyrate Treatment of 2 Patients With Monocarboxylate Transporter 8 Deficiency

Article

作者: Sonntag, Niklas ; Braun, Doreen ; Schweizer, Ulrich ; Banne, Ehud ; Zung, Amnon

AbstractContextMonocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency.ObjectiveWe aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency.MethodsWe treated 2 monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, vital signs, anthropometric measurements, and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients had received in the past.ResultsNaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neurocognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range, but elevated liver transaminases were observed.ConclusionIn the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body mass index, with minor neurodevelopmental changes.

2024-08-01·Thyroid®

3,3′,5-Triiodothyroacetic Acid Transporters

Article

作者: de Rooij, Linda J ; Hamers, Timo ; Yildiz, Sena ; Leeuwenburgh, Selmar ; Meima, Marcel E ; Markova, Boyka ; Chen, Zhongli ; Peeters, Robin P ; Heuer, Heike ; Visser, W Edward

Introduction: Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter (MCT) 8 is a key transporter and is expressed at the blood-brain barrier (BBB), in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays because of cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3',5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human BBB and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and Methods: Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate-buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. Results: In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (n = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n = 19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6, and SLC22A24 (in DMEM). The zebrafish and mouse orthologs of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but was reduced at P120. Conclusions: Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8, and SLC22A24 as well as their mouse and zebrafish orthologs are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.

项与替拉曲可相关的新闻（医药）

2023-03-31

·FierceBiotech

What M&A slowdown? Buyers circle GreenLight Biosciences, Egetis Therapeutics

Both GreenLight and Egetis pointed out that they hadn't accepted an offer yet. While biotech M&A may have cooled down over the past year, no one has told GreenLight Biosciences or Egetis Therapeutics, which are both mulling takeover offers. RNA-focused GreenLight announced yesterday that it has received an offer from VC firm Fall Line Capital’s Fall Line Endurance Fund to acquire all outstanding stock of the biotech for 60 cents per share. GreenLight— which spreads itself across vaccines and therapies for humans as well as agricultural solutions—only went public via a special purpose acquisition company (SPAC) merger in February 2022. The merger agreement valued the company at $1.2 billion and GreenLight’s stock hit a high of over $12 per share in the following weeks. But it’s been dropping ever since, with a closing price Thursday of just 43 cents. Still, the biotech emphasized that no sale has been agreed yet, with the company’s board of directors due to “carefully evaluate Fall Line’s indication of interest within the context of the ongoing review of various alternatives and in consultation with any financial and legal advisors it may retain.” GreenLight ended 2022 with $68.1 million in cash and equivalents. Despite pausing its gene therapy program for sickle cell anemia and cutting 25% of staff in October 2022 to save money, the company still expects reserves to run dry by June. The biotech had already announced it was looking at a range of measures to eke out its runway, including “further management of program spending, additional platform licensing collaborations and potential further financing activities.” Even with human health ambitions now limited to preclinical vaccine candidates for pan-sarbecovirus and shingles, as well as a cancer vaccine collab with EpiVax, it’s not surprising the company is open to external offers. Less is known about Egetis’ offer. The biotech released a concise note yesterday responding to “existing rumors” by confirming that the company “has ongoing discussions with certain external parties regarding a potential acquisition.” Again, Egetis was keen to stress that no offer has yet been agreed. The Swedish company’s lead product is Emcitate, which is in phase 2 trials for Allan-Herndon-Dudley syndrome, a rare genetic disorder that impacts a child's cognition, mobility and overall health and for which there is currently no available treatment. Egetis plans to submit a request for EU approval in the second quarter of the year based on existing clinical data.

疫苗并购临床2期

2021-02-27

·药融圈

40款新药研发有新进展，国产康希诺新冠疫苗重磅来袭！感染领域再发力，涉及康希诺、康泰、瑞科、默沙东、拜耳等！

▲速抢免费参会名额 | 大湾区(广州)生物医药创新者峰会导语根据公开资料不完全统计，药融云为大家检测到了2021年2月16日至2021年2月22日的全球新药重大研发进展40条。其中涉及药物上市2条，药物提交上市申请4条，临床重大进展33条，2款药物研究终止。 9款治疗“新型肺炎冠状病毒感染(COVID-19)”的药物研发阶段发生重大进展，康希诺和拜耳提交上市申请。根据《疫苗管理法》、《药品管理法》相关规定，新冠疫苗按照药品特别审批程序，进行应急审评审批，而且新冠疫苗的研发过程中企业就与药审中心进行滚动资料提交，因此从递交上市申请到获批上市用时非常短，预计康希诺Ad5-nCoV近期也会加快获批上市。康希诺的新冠疫苗上市申请获受理，康希诺生物B盘中大涨逾10%。数据来源：东方财富网表1 40款药物基本信息数据来源：药融云全球药物研发数据库据统计，40款药物的治疗领域主要是感染、肿瘤等。据统计，40款药物的适应症主要是新型肺炎冠状病毒感染(COVID-19)。表2 40款药物适应症(TOP10) 数据来源：药融云全球药物研发数据库上市药物生物药evinacumab（依维苏单抗）和rVSV-EBOV获批上市。 01 evinacumab（依维苏单抗）近日，FDA批准再生元研发的evinacumab上市，用于治疗纯合子家族性高胆固醇血症（HoFH）。人源化单克隆抗体evinacumab是一种血管生成素相关蛋白-3（ANGPTL3）抑制剂，曾获“突破性疗法（2017年）、快速通道、孤儿药、儿科用药研究计划、优先审评（2020年）”资格认定。 evinacumab之所以可以降低HoFH患者的胆固醇含量，是因为它主要靶向ANGPTL3，可以有效抑制蛋白脂肪酶和内皮质酶，并且可以在脂蛋白的代谢中起到关键作用。由于evinacumab的独特靶点和作用机制，再生元还正在进行evinacumab 治疗“顽固型高胆固醇血症”和“重度高甘油三酯血症”的二期临床试验。 evinacumab的获批是基于一项评估evinacumab治疗HoFH的疗效性和安全性试验。此项试验，65例HoFH患者被随机分为两组：evinacumab组（43例）和安慰剂组（22例）。在基线时，evinacumab组和安慰剂组患者的基线平均低密度脂蛋白胆固醇（LDL-C）水平相似，分别为259.5mg/dl和246.5 mg/dl。evinacumab组患者每4周静脉注射evinacumab 15mg/kg，为期24周。主要终点为基线至24周时LDL-C的降低。研究显示，在第24周时，evinacumab组患者的LDL-C水平降低了47.1%，安慰剂组则增加了1.9%（LS平均差异为-49.0%，P＜0.0001）。 evinacumab的获批对于HoFH患者是一个分水岭，为HoFH患者提供了新的治疗选择。根据药融云全球药物研发数据库预测，evinacumab未来5年的销售额有可能会逐年增加，预计今年的销售额可达到0.12亿万美元，2025年或可达到1亿美元。 02 rVSV-EBOV 近日，默沙东研发的治疗“埃博拉病毒传染”的糖蛋白rVSV-EBOV在多个国家/地区上市，曾获“加速批准、突破性疗法、优先审评、EMA优先药物”。rVSV-EBOV最初由加拿大微生物实验室公共卫生署研发，之后授予默沙东研发和市场化权利。根据药融云全球药物研发数据库预测，rVSV-EBOV未来5年的销售额有可能会逐年增加，预计今年的销售额可达到0.3亿万美元，2025年或可达到1亿美元。提交上市申请的药物 Ad5-nCoV、omalizumab biosimilar（奥马珠单抗类似药）、SARS-CoV-2 mRNA vaccine和ARI-0001提交上市申请。 01 Ad5-nCoV 康希诺生物与中国人民解放军军事医学科学院生物工程研究所合作研发的COVID19刺突糖蛋白调节剂Ad5-nCoV提交上市申请，用于治疗“新型肺炎冠状病毒感染(COVID-19)”，曾获“紧急使用授权”资格。 Ad5-nCoV的Ⅲ期临床试验结果显示：在单针接种疫苗28天后，疫苗对所有症状的总体保护效力为65.28%；在单针接种疫苗14天后，疫苗对所有症状总体保护效力为68.83%。疫苗对重症的保护效力分别为：单针接种疫苗28天后为90.07%；单针接种疫苗14天后为95.47%。康希诺生物新冠疫苗接种一针即可提供保护力。储运条件也相对便捷，从目前的研究结果来看，在2-8℃ 条件下可稳定保存至少3个月，在25℃条件下可稳定保存至少2个月，在37℃ 条件下可稳定保存至少3周。目前，国内已经有两款疫苗获批附条件上市，均为灭活疫苗，分别来自国药集团中国生物和北京科兴。如果本次康希诺生物最终顺利获批，则意味着将成为国内获得附条件上市的第三款疫苗，同时也是国内获批的首款腺病毒载体新冠疫苗。 02 omalizumab biosimilar（奥马珠单抗类似药）人源化单克隆抗体奥马珠单抗类似药是一款治疗哮喘的免疫球蛋白E拮抗剂。 03 SARS-CoV-2 mRNA vaccine 拜耳研发的SARS-CoV-2 mRNA vaccine 是一款治疗新型肺炎冠状病毒感染(COVID-19)和SARS病毒感染的COVID19刺突糖蛋白调节剂。 04 ARI-0001 B淋巴细胞抗原CD19调节剂ARI-0001是一款治疗“急性淋巴细胞白血病、慢性淋巴细胞白血病、非霍奇金淋巴瘤”的嵌合抗原受体T细胞疗法，此次提交上市申请的适应症是“急性淋巴细胞白血病”。进入临床三期的药物 glofitamab、upamostat、Mim-8、tiratricol（替拉曲考）和posoleucel进入临床三期。 01 glofitamab 罗氏研发的glofitamab是双特异性T细胞衔接子抗体，用于治疗“B淋巴细胞瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、多发性骨髓瘤、非霍奇金淋巴瘤”。此次进入临床三期的适应症是“弥漫性大B细胞淋巴瘤”。 glofitamab是靶向CD20和CD3的双特异性抗体，靶向B细胞表面的CD20和T细胞表面的CD3。其中CD20位点使用的是二代人源化CD20单抗奥妥珠单抗的位点。基于一种新颖的结构形式，称之为“ 2：1”，指的是具有两个与CD20结合的“ Fab”区域和一个与CD3结合的“ Fab”区域。这种结构的优势在于glofitamab能够与B细胞表面CD20的结合性更高。即使肿瘤细胞表达CD20含量较低，glofitamab也可以找到肿瘤细胞发挥作用。CD20和CD3首尾相连的结构也可以诱导快速T细胞活化、增殖、细胞因子释放，导致靶细胞裂解。而且“ 2：1”的结构形式也能够使glofitamab与其他抗CD20抗体联用，为后续研发联合治疗方案提供可能性。 02 upamostat RedHill Biopharma Ltd研发的upamostat是一种新型且有效的胰蛋白酶、丝氨酸蛋白酶抑制剂，靶向参与为病毒侵入目标细胞准备刺突蛋白的人类细胞因子，有望有效对抗新出现的带刺突蛋白突变的病毒变种，用于治疗“乳腺肿瘤、新型肺炎冠状病毒感染(COVID-19)、胃肠道炎症、胃肠道肿瘤、胰腺肿瘤”，曾获“孤儿药”资格认定。此次进入临床三期的适应症是“新型肺炎冠状病毒感染(COVID-19)”。近日，RedHill Biopharma Ltd宣布，其研发的口服胶囊upamostat在美国启动三期临床试验，该实验旨在评估upamostat治疗轻症新冠肺炎患者的疗效。 03 Mim-8 诺和诺德研发的免疫球蛋白G同型抗体Mim-8，是一种凝血因子IX和X拮抗剂，用于治疗“凝血因子VIII缺乏症”。 04 tiratricol（替拉曲考） Rare Thyroid Therapeutics International AB研发的tiratricol用于治疗“X连锁遗传病”，甲状腺激素受体激动剂，曾获“孤儿药、罕见儿科疾病用药”资格认定。 05 posoleucel AlloVir研发的posoleucel，是一种T淋巴细胞疗法，用于治疗“腺病毒感染、BK病毒感染、膀胱炎、巨细胞病毒感染、EB病毒感染、造血干细胞移植、疱疹病毒6型感染、多瘤病毒感染”，曾获“孤儿药、EMA优先药物、再生医学先进疗法”资格认定。此次进入临床二期的适应症是“巨细胞病毒感染、腺病毒感染、BK病毒感染、EB病毒感染、多瘤病毒感染、疱疹病毒6型感染”。版权声明：本文转自药融云，如不希望被转载的媒体或个人可与我们联系，我们将立即删除【关于药融圈】药融圈围绕我国生物医药产业链，针对生物医药大数据、技术和资本投资、药融园(产业园)等开展系列系统性工作，促进我国生物医药产业健康发展，完善产业链，共同面对全球合作和竞争。点分享点点赞点在看